Enhanced Mammalian Transmissibility of Seasonal Influenza A/H1N1 Viruses Encoding an Oseltamivir-Resistant Neuraminidase
Enhanced Mammalian Transmissibility of Seasonal Influenza A/H1N1 Viruses Encoding an Oseltamivir-Resistant Neuraminidase
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DOI：
10.1128/jvi.07242-12
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发表时间：
2012-07-01
影响因子：
5.4
通讯作者：
Pica, Natalie
中科院分区：
文献类型：
--
作者：
Bouvier, Nicole M.;Rahmat, Saad;Pica, Natalie
2007年至2009年间，季节性甲型H1N1流感（sH1N1）病毒分离株对奥司他韦的耐药性呈指数级增长，但奥司他韦的使用量却没有相应增加。我们假设，耐奥司他韦的神经氨酸酶（NA）除了相对不易受奥司他韦的抗病毒作用影响外，还可能通过提高这些病毒在人类中的传播效率而赋予这些病毒额外的适应性优势。在这里，我们证明了一种对奥司他韦耐药的临床分离株，即 2008 年在纽约州分离出的一种 A/布里斯班/59/2007(H1N1) 样病毒，与高度相似的同期奥司他韦敏感分离株相比，在豚鼠中的传播效率更高。通过两个临床分离株的反向遗传学重配体和点突变体，我们进一步表明，在奥司他韦敏感病毒（7:1 重配体）的病毒蛋白背景下，奥司他韦耐药 NA 的表达足以增强传播性。在豚鼠模型中，NA 是奥司他韦敏感型和耐药型 Brisbane/59 型 sH1N1 病毒之间传播效率的关键决定因素，与其他基因产物中同时发生的漂移突变无关。我们的数据表明，对奥司他韦耐药的 NA（具体来说，伴随突变 H275Y 和 D354G 之一或两者）可能使耐药 Brisbane/59 样病毒的传播能力超过了敏感分离株。这些数据提供了进化机制的体内证据，该机制可以解释人类储存库中的 sH1N1 分离株中奥司他韦耐药性如何迅速实现固定。
Between 2007 and 2009, oseltamivir resistance developed among seasonal influenza A/H1N1 (sH1N1) virus isolates at an exponential rate, without a corresponding increase in oseltamivir usage. We hypothesized that the oseltamivir-resistant neuraminidase (NA), in addition to being relatively insusceptible to the antiviral effect of oseltamivir, might confer an additional fitness advantage on these viruses by enhancing their transmission efficiency among humans. Here we demonstrate that an oseltamivir-resistant clinical isolate, an A/Brisbane/59/2007(H1N1)-like virus isolated in New York State in 2008, transmits more efficiently among guinea pigs than does a highly similar, contemporaneous oseltamivir-sensitive isolate. With reverse genetics reassortants and point mutants of the two clinical isolates, we further show that expression of the oseltamivir-resistant NA in the context of viral proteins from the oseltamivir-sensitive virus (a 7:1 reassortant) is sufficient to enhance transmissibility. In the guinea pig model, the NA is the critical determinant of transmission efficiency between oseltamivir-sensitive and -resistant Brisbane/59-like sH1N1 viruses, independent of concurrent drift mutations that occurred in other gene products. Our data suggest that the oseltamivir-resistant NA (specifically, one or both of the companion mutations, H275Y and D354G) may have allowed resistant Brisbane/59-like viruses to outtransmit sensitive isolates. These data provide in vivo evidence of an evolutionary mechanism that would explain the rapidity with which oseltamivir resistance achieved fixation among sH1N1 isolates in the human reservoir.